Protegrin

Identifiers
Symbol N/A
OPM superfamily 226
OPM protein 1pg1

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses.[1] The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues.[2] Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues.[3] Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.[4]

Structure

There are five known porcine protegrins, PG-1 to PG-5.[5] Three were identified biochemically and rest of them were deduced from DNA sequences.[6]

Protegrin structures

The protegrins are synthesized from quadiripartite genes as 147 to 149 amino acid precursursors with a cathelin-like propiece.[5][7] Protegrin sequence is similar to certain prodefensins and tachyplesins, antibiotic peptides derived from the horseshoe crab.[1] Protegrin-1 that consists of 18 amino acids, six of which are arginine residues, forms two antiparallel β-sheets with a β-turn. Protegrin-2 is missing two carboxy terminal amino acids. So, Protegrin-2 is shorter than Protegrin-1 and it has one less positive charge. Protegrin-3 substitutes a glycine for an arginine at position 4 and it also has one less positive charge. Protegrin-4 substitutes a phenylalanine for a valine at position 14 and sequences are different in the β-turn. This difference makes protegrin-4 less polar than others and less positively charged. Protegrin-5 substitutes a proline for an arginine with one less positive charge.[5]

Mechanism of Action

Protegrin-1 induces membrane disruption by forming a pore/channel that leads to cell death.[8][9] This ability depends on its secondary structure.[10] It forms an oligomeric structure in the membrane that creates a pore. Two ways of the self association of protegrin-1 into a dimeric β-sheet, an antiparallel β-sheet with a turn-next-totail association or a parallel β-sheet with a turn-next-toturn association,[11] were suggested. The activity can be restored by stabilizing the peptide structure with the two disulfide bonds.[12] The interacts with membranes depends on membrane lipid composition[13] and the cationic nature of the protegrin-1 adapts to the amphipathic characteristic which is related to the membrane interaction.[9] The insertion of Protegrin-1 into the lipid layer results in the disordering of lipid packing to the membrane disruption.[13]

Antimicrobial Activity

The protegrins are highly microbicidal against Candida albicans,[14] Escherichia coli,[15]Listeria monocytogenes, Neisseria gonorrhoeae[16] , and the virions of the human immunodeficiency virus in vitro under conditions which mimic the tonicity of the extracellular milieu.[1][5][17] The mechanism of this microbicidal activity is believed to involve membrane disruption, similar to many other antibiotic peptides [5][18]

References

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  1. 1 2 3 Kokryakov, V.N.; Harwig, S.S.L.; Panyutich, E.A.; Shevchenko, A.A.; Aleshina, G.M.; Shamova, O.V.; Korneva, H.A.; Lehrer, R.I. (1993), "Protegrins:leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins.", FEBS Letters 327 (2): 231–236, doi:10.1016/0014-5793(93)80175-T, PMID 8335113
  2. ↑ Jang, H.; Ma, B.; Nussinov, R. (2007), "Conformational study of the protegrin-1 (PG-1) dimer interaction with lipid bilayers and its effect", BMC Structural Biology 7: 21, doi:10.1186/1472-6807-7-21, PMC 1858697, PMID 17407565
  3. ↑ Kandasamy, S.K.; Larson, R.G. (2007), "Binding modes of protegrin-1, a beta-strand antimicrobial peptide, in lipid bilayers", Molecular Simulation, 33 9 (10): 799–807, doi:10.1080/08927020701313737
  4. ↑ Yasin, B.; Harwig, S.S.; Lehrer, R.I.; Wagar, E.A. (1996), "Susceptibility of Chlamydia trachomatis to protegrins and defensins", Infection and immunity 64 (3): 709–713, PMC 173826, PMID 8641770, retrieved 2009-04-25
  5. 1 2 3 4 5 Miyasaki, K.T.; Iofel, R; Lehrer, RI (1997), "Sensitivity of periodontal pathogens to the bactericidal activity of synthetic protegrins,", Journal of Dental Research 76 (8): 1453–1459, doi:10.1177/00220345970760080701, PMID 9240381
  6. ↑ Zhao, C.; Ganz, T.; Lehrer, R.I. (1995), "The structure of porcine protegrin genes", FEBS Letters 368 (2): 197–202, doi:10.1016/0014-5793(95)00633-K, PMID 7628604
  7. ↑ Zhao, C.; Liu, L.; Lehrer, R.I. (1994), "Identification of a new member of the protegrin family by cDNA cloning", FEBS Letters 346 (2–3): 285–288, doi:10.1016/0014-5793(94)00493-5, PMID 8013647
  8. ↑ Panchal, R.G.; Smart, M.L.; Bowser, D.N.; Williams, D.A.; Petrou, S. (2002), "Pore-forming proteins and their application in biotechnology", Current Pharmaceutical Biotechnology 3 (2): 99–115, doi:10.2174/1389201023378418, PMID 12022262
  9. 1 2 Sokolov, Y.; Mirzabekov, T.; Martin, D.W.; Lehrer, R.I.; Kagan, B.L. (1999), "Membrane channel formation by antimicrobial protegrins", BBA Biomembranes 1420 (1–2): 23–29, doi:10.1016/S0005-2736(99)00086-3, PMID 10446287
  10. ↑ Drin, G.; Temsamani, J. (2002), "Translocation of protegrin I through phospholipid membranes: role of peptide folding", BBA Biomembranes 1559 (2): 160–170, doi:10.1016/S0005-2736(01)00447-3, PMID 11853682
  11. ↑ Fahrner, R.L.; Dieckmann, T.; Harwig, S.S.L.; Lehrer, R.I.; Eisenberg, D.; Feigon, J. (1996), "Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes", Chemistry & Biology 3 (7): 543–550, doi:10.1016/S1074-5521(96)90145-3
  12. ↑ Lai, J.R.; Huck, B.R.; Weisblum, B.; Gellman, S.H.; Others (2002), "Design of non-cysteine-containing antimicrobial beta-hairpins: structure-activity relationship studies" (PDF), Biochemistry 41 (42): 12835–12842, doi:10.1021/bi026127d, PMID 12379126, retrieved 2009-04-27
  13. 1 2 Gidalevitz, D.; Ishitsuka, Y.; Muresan, A.S.; Konovalov, O.; Waring, A.J.; Lehrer, R.I.; Lee, K.Y.C. (2003), "Interaction of antimicrobial peptide protegrin with biomembranes", Proceedings of the National Academy of Sciences 100 (11): 6302–6307, doi:10.1073/pnas.0934731100, PMC 164441, PMID 12738879
  14. ↑ Cho, Y.; Turner, J.S.; Dinh, N.N.; Lehrer, R.I. (1998), "Activity of Protegrins against Yeast-Phase Candida albicans", Infection and immunity 66 (6): 2486–2493, PMC 108228, PMID 9596706
  15. ↑ Lehrer, R.I.; Barton, A.; Daher, K.A.; Harwig, S.S.; Ganz, T.; Selsted, M.E. (1989), "Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity", Journal of Clinical Investigation 84 (2): 553–61, doi:10.1172/JCI114198, PMC 548915, PMID 2668334
  16. ↑ Qu, X.D.; Harwig, S.S.; Oren, A.M.; Shafer, W.M.; Lehrer, R.I. (1996), "Susceptibility of Neisseria gonorrhoeae to protegrins", Infection and Immunity 64 (4): 1240–5, PMC 173910, PMID 8606085, retrieved 2009-04-27
  17. ↑ Tamamura, H.; Murakami, T.; Horiuchi, S.; Sugihara, K.; Otaka, A.; Takada, W.; Ibuka, T.; Waki, M.; et al. (1995), "Synthesis of protegrin-related peptides and their antibacterial and anti-human immunodeficiency", Chemical & pharmaceutical bulletin 43 (5): 853–8, doi:10.1248/cpb.43.853, PMID 7553971
  18. ↑ Gabay, J.E. (1994), "Ubiquitous natural antibiotics", Science 264 (5157): 373–374, doi:10.1126/science.8153623, PMID 8153623
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